DE1493357B1 - Process for the preparation of prostaglandins and prostaglandin-like compounds - Google Patents

Description

The invention relates to a process for the microbiological conversion of certain unsaturated fatty acids with two 1,4-permanent double bonds in cyclopentylalkanoic acids with a prostaglandin or prostaglandin-like effect.

You erfisdu0g * eemäOe method is characterized in that one uses an unsaturated fatty acid of the formula Cif ^ & l- CH ₂ -HO CH- C ¹ H ₁ - ^ H = CH-CH ₂ - CH- GH-CH, - CH *

, ■ .-. ■ i 'fi

CH

ie the the Iteioaipt btw. the S- and 17-permanent MppeflfeKhme gegtitaeiifalli can be hydrogenated, or their satefe in an aqueous medium at a temperature between about 20 and 40 ° C and a pH value of about 6.5 to 8.0 aerobically treated with shredded sheep's bark tissue and the prostaglandins or prostaglandin-like compounds are isolated in a known manner from the aqueous reaction femjsch;

The term »prostaglandin« refers to a material with a wootdrock-lowering effect and a stimulating effect on the smooth muscles. Sperm and dgj. is won. The antihypertensive effect was * by J a pel Ii and Sc ο pa im Year 1906 (Arch. Ital. Biol., Vol. 45, 1906. p. 165) an extract from canine prostate glands.

Antihypertensive and smooth muscle stimulating effects were also found in similar extracts, namely by Kurzrok in 1930 (Proc. Soc. Exp. Biol. NY, Vol. 28. 1930. p. 268), G o 1 db I a 1 1 in 1933 (Chem. e Ind., Vol. 52, 1933, p 1056) and e u 1 er in the years 1931 to 1936 (Arch. Exp. Path. Pharmak, Vol. 175, 1934, S 78; Vol. 181, 1936, p. 181: J. Physiol :, Vol. 72, 1931, p. 74; Vol. 81, 1934. p. 102; Vol. 84, 1935. p. 21: Vol. 88, 1936, p. 213: Klin. Wschr., Vol. 14. 1935, p. 1182).

More recently (Acta Chemica Scandinavia, Vol. 14.1960, pp. 1693-1704 ) , two particular compounds called PGE and PGF have been made from raw materials. L. B. Euler's prostaglandin, isolated. The two compounds have the following structural formulas:

OH

PGE (referred to as PGE according to the newer nomenclature)

HOOC-CH ₂ -CH ₂ -Ch ₂ -CH ₂ -CH ₂ -CH ₂ CH = CH-CH-CH ₂ -CH ₂ -CH ₂ -CH ₂ -Oh ₃

== 7- [3 "-Hydroxy-2- (3-hydroxy-1-octenyl) -5-oxocyclopentyl] -heptanoic acid.

PGF (referred to as PGF according to the newer nomenclature) OH

HOOO-CH ₂ -Oh ₂ -CH ₂ -CH ₂ -CH ₂ -CH ₂ CH = OH- ³ CH CH ₂ -CH ₂ CH ₂ -CH ₂ -CH ₃

\ r- OH

= 7- [3 ".5" -dihydroxy-2- (3-hydroxy-1-octenyl) -c> elopentyl] -heptanoic acid.

The broken lines in the above formulas indicate. that the substituents in question are -position. ie located below the level of the cyclopentane ring. The PGE, compounds have a keto group in the 5-position of the cyclopentane ring _{, whereas the PGF 1} , compounds have a hydroxyl group. Further compounds of the PGE and PGF series are referred to as PGE, and PGF ,,, with reference to their relationship. Reduction of PGE with sodium borohydride gives PGF ₁ ,, and its / i-epimers, PGF ,, <. in which the hydroxyl group is in the 5-position of the cyclopentane ring / f position.

BATH ORIGINAL

PGE ₁ . On _{hydrogenation, PGF 1} and PGF ₁ give the corresponding saturated acids, namely:

Dihydro- PGE,

= 7- [3 «-Hydroxy-2- (3-hydroxy-octyl) -5-oxocyclopentyij-heptanoic acid:

Dihydro-PGF _1;,

- 7- [3 ", 5" -dihydrate> x> -2- (3-h) droxy-oci> l) -cyclopentylj-heptunic acid:

Dihydro-PCiF _1. , ·

= 7- [3 ".5 ₎ z-Dihydroxy-2- (3-hydroxy-octyl) -cyclopent) l] -heptanoic acid.

I 493

All of these dihydric acids have the same or similar effectiveness as PGE, and PGF, ..

Various hydrogen derivatives of PGE ₁ and PGF _{14 are also} known, the subscript number in the following names indicating the number of double bonds in the molecule:

Tetradehydro-PGF _U = PGF ,. CJDhÄh

, ^ = PGFj d ^?

IO

, = PGF ₃ ,

^^^ Jdroxy-2- {y cyclopentyO ^ hcpten & aure yl> 5-hcpt «eiun :.

Alk TOrstdteBd lu ^ fWirt »» acids as well Eater upd sofa «thawed the ffir dwErivrscbe ft» * »-

\ fenkuiatur w Wirftam & the i »d * r rtaofcfollowing g aft profstaetaadmartig Wicliuag beasekhnef wiri,

<3e (eraUHMl ddr Erimbmg Mt ι

binding through microbiological conversion «on 8.11,14-eicosatrien-, 5,8,1 l, 14-Ek »» tetraen- (= j chidon-) and 5.8; H.14.17-eicosape-satanic acid.

The substrate is subject to a ring closure reaction according to the following scheme:

AB AB

(I)

(II)

where A B.

HOOC - (CH, b - CH - = CH - CH, - CH ₂ - CH = CH - CH ₂ - CH == CH - CH ₂

X and X 'are hydroxyl groups. X keto oxygen and X ' the hydroxyl group or X 'is keto oxygen and X is the hydroxyl group. The exact reaction mechanism of this conversion is not known. however, it could take place in the following way:

CH ₃

(C)

B '

; s

O-

-O

(I)

(II) in which A has the above meaning and A '. B 'and B "are those around the cited sections reduced substituents A and B mean. To the Example is obtained when using the compound of the general formula (al in the invention Process as the main product a compound of the general formula

In this assumed reaction mechanism, the compound of the formula I is initially converted into the cyclic endoperoxide of the general formula (I (converted, which is then converted into the 3.5-dioxydated Product of the general formula (III is converted.

In addition to the cyclization and the oxidation in the 3- and 5-position of the cyclopentane ring formed can in the process according to the invention also oxidations at one or more points in chains A and or B. These oxidations take place in particular on the unsaturated bonds through a methyl group from the 1.4-diene moiety are separated, namely in the fatty acid structures:

4?

- B 'OH

so in which X and X 'have the meaning given above to have.

The compound of the general formula (b) gives the following compounds:

A-

(a)

OH

and

(b) A'-

OH OH

X \ - X '

BATH ORIGINAL

Similarly, one obtains from the compound of the general formula (c) the following products

OH

OH B.

OM

OH

It was found that the oxidation in the Chains A and B are easiest to separate when those of the 1.4 double bonds go through a methylene group separate double bonds have cis-conguration.

To carry out the method according to the invention, the starting material is aerobic Conditions incubated with sheep bladder gland tissue and a material from the mixture obtained with prostaglandin b / w. prostaglandin-like activity isolated.

In the case of the unsaturated acids used as the starting material, c-> are ones that are normally found in animal tissue but also from other (sources

The whole, freshly frozen glands of the slaughtered animals are first crushed is generally made in a meat grinder of a suitable size. Other ingredients can also be used The glands are preferably applied frozen at a temperature below about -3d C, and / wai essentially immediately after their Isolation from your animal body. This can be done in different ways, ζ. Β by storing of the glands, immediately after their removal from the carcass, in one with liquid nitrogen tnler solid carbon dioxide cooled container other However, metals for cooling to temperatures below about OC are also satisfactory Most expedient it is of course the glands to keep them at these low temperatures until they are used in the process according to the invention, since they can be stored in this form, until a sufficient supply is available and they are also easier to transport. Fs was fernei found that the effectiveness of the glands tied up is greater in the method according to the invention. if it was frozen immediately after removal from the frigidly slaughtered animal.

The ground glandular tissue and the unsaturated fatty acids to be converted are intimately mixed with one another, e.g. B by vigorous stirring or Homogenize. An aqueous nutrient medium is then added to the mixture. You can also do that Mix the crushed glands with the nutrient medium before adding the starting material. That obtained mixture is bc · preferably about λ "/ (

d. h body temperature, but temperatures between about 20 and 40 C can also be used. The aqueous nutrient medium mentioned above and / or required to carry out the conversion can consist of body fluids, ζ. Β from blood or plasma, or from a weakly alkaline physiological saline solution, such as a Krebs-Ringer solution, which ι. B has been adjusted to a pH of about 7.4 with sodium bicarbonate. a Ringer's phosphate buffer solution or other physiological saline solution, or an aqueous solution. the bacteriostatic amounts of alcohol, e.g. B up to about 20 "", or even from water with traces of mineral salts and other elements normally found in tap water. The pH of the medium is preferably slightly alkaline, ie it is about 7.4. however, pH values between about 6.5 and XO are also possible. The nutrient medium can also contain (.'ofactors. Which contain an adenine or nicotiric acid amide residue. Their presence obviously increases the yields and is therefore preferred. Examples of suitable (ofactors are nicotinic acid amide. (Vtochrom (. Na adenosine triphosphate. ( oenzvm I (Diphosphoivridine-nucleotidt. "FAD" (Ilavine-adenine-dinucleolidi and adrenocorticotropic hormone (A (THl With nicotinic acid the highest bulges are obtained

The fatty acid used as the starting material The gland suspension can be in the form of the free acid or as a salt, ζ B as sodium. Potassium or ('alciunisal /. to be added.

The incubation takes place under aerobic conditions, i.e. in the presence of oxygen, which is why the reaction mixture is stirred at least from time to time I iii must graze the supply of saunas Such occasional stirring is sufficient. but is preferably a suucrsiofThaltigcs (i.is in d.is Rcaklion> mixture introduced Fs can Oxygen or oxygen-containing gases in any in sufficient quantities to maintain aerobic conditions. The degree the ventilation can depend on the amount of driiscni: ewehes or dun volume of the Rlalti'iiisgemisches vary considerably between about 0.1 and 5 liters of oxygen per pus solution are satisfactory. Preferably between about 0.5 and about 5 liters of oxygen per pus solution applied. The elimination of a diluent, such as carbon dioxide, nitrogen or helium, obviously has no disadvantages varies considerably according to the degree of ventilation and the ratio of the nozzle tissue The unsaturated acids are generally sufficient Reaction times of 2 to 5 hours for conversion the unsaturated acids in prostaglandins and similar compounds. when these acids are off other sources are added to the outside of the glands. «.Iiircn iiiii are present in the tissue itself and no further addition ν on takes place outside, is that for oxidation required time considerably longer, probably on Because the unsaturated fatty acids are bound to the tissue, willow does not contain any unsaturated fatty acids supplied from the outside, the response time is bi> up to 40 and even up to 144 hours. Here is Note that excessive ventilation over a Itrnirv time probably one, n.tchteiiieen I in

BATH ORIGINAL

river exercises. Other variables also influence the Conversion and yield of prostaglandin or prostaglandin-like compounds, e.g. B. the season in which the glandular tissue was isolated, the Health status of the animals from which the glands originate, the presence of cofactors in the nutrient medium and, in particular, the nutrient medium itself.

If an aqueous alcohol is used as a nutrient medium and ventilated during the incubation, so is it is advisable to add more alcohol at a later stage to avoid evaporation loss balance. With longer response times of z. B. about 4 to 144 hours, the addition of an agent preventing the decomposition of the glands is appropriate. Bacteriostatic agents are suitable for this, such as alcohols, toluene, benzene, benzoates, quaternary ammonium salts or chlorobutanol. Also the adjustment of the pH value to a certain range as well as other measures to prevent decomposition can be used. An advantageous one Method consists in the use of an alcoholic medium with a content of up to about 20% Alcohol, with the alcohol partly as a nutrient medium and partly as an agent preventing decomposition works.

The ratio of the unsaturated fatty acids to the glandular tissue or vice versa is obviously not critical because in the conversion of unsaturated fatty acids into prostaglandin and similar compounds weight ratios of glandular tissue too unsaturated fatty acids from only SO: 1 up to 2000: 1 led to satisfactory results. Lower and higher ratios can also be used, and with a weight ratio of only 10 parts glandular tissue per 1 part becomes more unsaturated Fatty acid achieved satisfactory results.

The desired, prostaglandin- or prostaglandin-like effect exhibiting material is isolated from the reaction mixture by conventional methods, eg. B. using the method described in US Pat. No. 3,069,322 for the isolation of prostaglandins PGE ₁ and PGF ₁ ,, from powder extracts. The reaction mixture can first be clarified in the usual way, e.g. B. by filtration or centrifugation, whereupon the clarified solution is concentrated. The resulting aqueous mixture is extracted with a water-immiscible solvent, such as methylene chloride, chloroform, carbon tetrachloride, ethylene chloride, trichlorethylene, ether, ethyl acetate, amyl acetate or benzene, and the solvent extract is evaporated to dryness. The acid mixture obtained is in a conventional manner, for. B. by chromatography or countercurrent distribution, separated. It is advantageous to work with hydrophilic and lipophilic solvents and aqueous buffer solutions using the different polarity of the individual compounds due to the additional hydroxyl group in the PGF compounds and the more unsaturated character of the bisdehyde and tetradehydro-PGE and bisdehyde-PGF compounds (Bisdehydro - PGF>PGF>Tetradehydro-PGE>Bisdehydro-PGE> PGE) to isolate and purify the dormant acids. For example, through fractional liquid-liquid extraction, such as countercurrent distribution or partition chromatography, homogeneous mixtures or individual compounds can be isolated from the crude extracts.

A preferred mode of operation is to extract the raw material containing the active ingredients, the acidic ingredients with a acid-affine material, e.g. B. an aqueous buffer solution or an anion exchange resin, in Be stirs and separates, the crude acids fractionated by multi-stage phase reversal partition chromatography, the first stage for separation the physiologically active acids from the inactive ones Acids under heavy loading and the later Stages are carried out under low loading in order to break down the mixture of active acids into its individual components. The extraction of the raw material is done purposefully moderately in two stages. First is with with water miscible alkanols, such as methanol, ethanol or isopropanol, extracted. The extracted Material transferred into a water-immiscible lipophilic solvent. To do this one narrows the alcoholic solution to an aqueous slurry and extracted the latter with a Water immiscible lipophilic solvent. Suitable lipophilic, immiscible with water Solvents are e.g. B. chlorinated hydrocarbons, such as methylene chloride, chloroform and ethylene dichloride; lower fatty acid esters such as ethyl acetate and Amyl acetate, higher alcohols, such as the water-immiscible lipophilic solvents Octanols; lower alka, immiscible with water none, such as methyl isobutyl ketone; Ether, such as dimethyl ether, diethyl ether, methyl isobutyl ether; aromatic hydrocarbons such as benzene or toluene. If desired, the water can also be used directly immiscible lipophilic solvent extracted

will. However, this is less advisable because the lower alcohols tend to be soluble proteins to denature and thus precipitate and non-polar

Not picking up materials so easily. The crude extracts obtained in this way then become

the carboxylic acids isolated. In general, these extracts are due to pharmacologically undesirable fats, Fatty acids and other products contaminated. These impurities are distributed one or more times between a lipophilic phase,

z. B. solutions in lipophilic solvents, such as those obtained during extraction, and a buffered one aqueous alkaline phase, e.g. B. aqueous phosphate, bicarbonate and tris (hydroxymethylamino) -mcth * n solutions removed. It can each have a pH

from about 8 to 9 buffered aqueous solution are used will. The lipophilic phase is extracted with the buffered aqueous phase, followed by the aqueous phase is acidified to a pH of about 3 to 4. This is followed by an introduction to the same

or another lipophilic solvent. Favorable distribution coefficients can be achieved through a suitable choice of the buffer pH value and the lipophilic solvent. The distribution between Buffer phase and lipophilic phase may optionally

take place in countercurrent. With a sufficient number of transfers, especially when using the less polar lipophilic solvents such as ether and a lower pH of e.g. about 8 the PGE acids are in the lipophilic phase and

the PGF acids are enriched in the buffer phase. In general it is not necessary and common also not desired to bring about a separation of the PGE and PGF connections at this stage.

009 514/189

to lead. Only all active acids should be extracted into the last buffer phase, whereupon they are in a volatile solvent, e.g. B. ether, are transferred, from which the crude acids by evaporation wins in a vacuum.

The increase in active material from one fraction to the next can be quantified by in vitro experiments due to the muscle-stimulating effect according to Eule r, Archive for Physiology, Vol. 77,

1957, pp. 96 to 99, can be followed. The total amount of fatty acids can be determined by microtitration with dilute alkali. The PGE acids (cyclopentanones) can easily be distinguished from the PGF acids (cyclopentanols) by their characteristic carbonyl ^{absorption band in the infrared absorption spectrum at 1730 cm "1} and their UV absorption at 280 ΐημ after the addition of alkali.

The active acids can also be obtained from anion exchange resins by adsorption and elution will. In this case, conversion into a water-immiscible solvent is expedient passed over. The extract obtained with water-miscible alkanols is applied directly to the Given ion exchange column. Suitable anion exchange resins are made by chloromethylation obtained from polystyrene cross-linked with divinylbenzene (see K u η i η, Ion Exchange Resins,

1958, pp. 88 and 97). The acids adsorbed can be eluted with solvents for acids, e.g. B. with those of the type mentioned above, those with hydrochloric acid or ammonium chloride acidified to pH 3-4. Aqueous solutions of with Water-miscible alkanols and ammonium chloride, e.g. B. a 50% solution of ammonium chloride

in 70% aqueous methanol can be used with success.

The crude acids obtained from the crude extracts by any of the above methods become then obtained by multi-stage reverse phase partition chromatography. If desired, can a conversion from a strongly non-polar solvent, such as petroleum ether, into a hydrophilic solvent, preferably an aqueous solution of a water-miscible alkanol, are interposed, to achieve a separation of the less polar impurities. When extracting the non-polar solvent solution with an aqueous alcoholic solution remain the less polar Components in the non-polar solvent. In multi-stage reverse phase partition chromatography the column is heavily loaded in the first stage in order to achieve a rough separation of the desired to effect active acids from the less polar components. The later stages are with the active fraction from the previous stage, but with a significantly lower load carried out so that an effective separation into the individual acids is achieved. The loading in the The first stage can be from about 50 to about 20 mg crude acid per gram of carrier during the loading should be less than about 25 mg acid per gram of carrier in the later stages. Suitable carriers for the separation columns are hydrophobic (treated with chloromethylsilane) or finely divided diatomaceous earth Low temperature polyethylene. The latter is used with advantage in the first stage. Through treatment with chloromethylsilane any diatomaceous earths commonly used as filter aids can be used be transferred to suitable carriers. It is advantageous to use the highly flowable types. If if desired, the PGE can be used in the intermediate fractions from a further fractionation for crystallization bring. The stationary phase of the separation column consists of a lipophilic, not water miscible solvents, the mobile phase from a hydrophilic solvent. The hydrophobic The carrier thus has an affinity for the stationary phase, but not for the mobile phase. Accordingly the more polar components are enriched in the mobile phase and the less polar components in the stationary phase. It any lipophilic and hydrophilic phases can be combined with one another for this purpose, their effectiveness depends on the distribution coefficient. An effective separation is achieved when the mobile phase consists of a solution of a water-miscible alkanol and water approximately the same proportions of about 3: 5 to 5: 3. Any lipophilic Solvents are used; however, a mixture of ratio- ^^ is preferably used moderately polar and non-polar solvents, ^ P z. B. a mixture of immiscible with water Alkanols or alkanones or lower fatty acid esters with hydrocarbons or chlorinated hydrocarbons. These two lipophilic solvents should also be in a ratio of 3: 5, up to 5: 3 are available. The mobile solvents and the stationary solvents are mixed and brought into a two-phase equilibrium. The stationary phase is then applied to the column, which Column with the preferably in a small amount of one of the phases, especially the mobile Loaded phase, dissolved or mixed with it, and the column with the mobile phase eluted.

If a solvent system consisting of a water-immiscible alkanol and water in the ratio 9:10 to 10: 9 and a water-immiscible alkanol and chloroform in the ratio 9:10 to 10: 9 can be used under the loading conditions described above, an effective separation of the PGE-acids in two stages of the phase Λ be achieved reverse partition. When the acids are eluted, the various components can be detected by in vitro tests, microtitrations or paper chromatography and the desired fractions can be combined for further processing or recovery of the fractionated component. .

The compounds obtainable with the process according to the invention not only have prostaglandin- or prostaglandin-like effect. They also control fertility, influence the central nervous system, regulate the salt and water balance, control the fat metabolism and set the cholesterol level down in the blood. Their last-mentioned property makes them valuable for preventing the onset of artherosclerosis. Because of their fat metabolism regulating effect, they can be used to combat obesity.

The salts of the compounds of alkali or alkaline earth metals, ammonia or basic amines that can be prepared according to the invention and their esters have the same pharmacological properties as the acids on which they are based.
BAD ORIQiNAL

The acids and their derivatives, alone or in admixture with others, can be used for therapeutic purposes active compounds, are converted into numerous oral and parenteral forms of administration, wherein solid and liquid carriers can be used.

The following examples explain the process according to the invention.

example 1

Sheep bladder glands were immediately removed from the freshly slaughtered animals Placing frozen in dry ice. 18.7 kg of the frozen glands were placed in a meat grinder ground and then to a mixture of 37.41 Krebs-Ringer solution (see Z. Physiol. Chem., Vol. 210, 1932, p. 33), which was adjusted to a pH of 7.4 with sodium bicarbonate, and 108 g of nicotinic acid amide given as a cofactor. 35.3 g of 5,8,11,14-eicosatetraenoic acid (arachidonic acid) were added to the mixture. added. The resulting suspension was mixed thoroughly for about 5 minutes, then into one Fermentation tank and kept at 37 ° C for 2 hours. A mixture became during the incubation of 95% oxygen and 5% carbon dioxide at a rate of about 8 l / min, through the suspension directed.

The reaction mixture was extracted three times with 100 liters of acetone within 24 hours. The used glands were then separated off and discarded. The acetone extracts were evaporated to dryness under reduced pressure. The residue was examined by paper chromatography and biological for its antihypertensive effect (cf. Horton and coworkers, op. Cit.) And its smooth muscle stimulating effect (Eu ler, op. Cit.). The main products were found to be PGF ₁₁ , PGF ₂ ", PGEi and PGE ₂ .

The resulting mixture was broken down into its main components as follows:

A five-stage countercurrent distribution was carried out between equal parts by volume of ether and 0.5 molar phosphate buffer solution with a pH of 6.4. The buffer phases were acidified and extracted three times with ether. All phases were evaporated to dryness, weighed and their physiological activity examined as indicated above. The residues containing the majority of the abovementioned main components were combined and each in the mobile phase of an isooctanol-chloroform-methanol-water mixture (1: 1: 10:10) in an amount of about 100 mg per 3 to 5 ml of the mobile phase Phase solved. A column in which 4 ml of the stationary phase of isooctanoI-chloroform-methanol-water (1: 1: 10: 10) on 4.5 g of hydrophobic diatomaceous earth (treated with chloromethylsilane) were contained was 100 mg of one with at least about Load 3 to 5 ml of the mobile phase mixed sample, whereupon the mobile phase was developed. The eluate fractions were examined for their smooth muscle stimulating effect according to E u 1 er. The fractions with maximum activity were evaporated. Essentially pure PGF ₁₃₁ , PGF ₂₁ , PGE ₁ and PGE _{2 were obtained} .

Repeating the above procedure using the sodium salt of 5,8,11,14-eicosatetraenoic acid gave essentially the same result.

It was also found that the use of 75 kg of sheep bladder glands and 37 g of 5,8,11,14-eicosatetraenoic acid gave a total of 13, Ig PGE ₂ , while using the same amount of sheep bladder glands in the absence of 5,8,11,14- Eicosatetraenoic acid, in addition to substantial amounts of endogenous PGE _1, only traces of PGE ₂ could be detected.

The use of 8,11,14-eicosatrienoic acid instead of 5,8,11,14-eicosatetraenoic acid and of glandular tissue with a content of 2.5 g of endogenous PGE ₁ resulted in a total of 8.5 g of PGE ₁ , that is, it was off of 8,11,14-eicosatrienoic acid 6.0 g of PGE.

Example 2

25% homogenized mixtures were prepared from sheep bladder glands. 250y 5,8,11,14,17-eicosapentaenoic acid was added to 2 ml of this, while a further 2 ml served as a control. The two samples were incubated, extracted after the incubation was complete, the extracts were chromatographed and the eluates were worked up. The absorption at 280 πΐμ after treatment with alkali resulted in the control sample being slightly above 3 γ PGE ₃ , for the sample mixed with 5,8,11,14,17-eicosapentaenoic acid more than 13 γ PGE ₃ .

Claims (2)

Patent claims: 1. Process for the production of prostaglandins and prostaglandin-like compounds, characterized in that an unsaturated fatty acid of the formula HOOO— (CH ₂ J ₃ -CH = -CH — CH ₂ -HC CH- £ h ₂ —CH = CH-CH ₂ -CH- CH- CH \ / * CH ₂ IO ' in which the 17-position or the 5- and 17-position double bond can optionally be hydrogenated, or their salts in an aqueous medium at a temperature between about 20 and 40 ⁰ C and a pH of about 6.5 to 6 s 8.0 treated aerobically with comminuted sheep bladder gland tissue and isolated the prostaglandins or the prostaglandin-like compounds from the aqueous reaction mixture in a known manner. 2. The method according to claim 1, characterized in that the aqueous medium contains up to about 20 percent by volume of ethanol. BAD ORiGINAL